Hypothermia Has No Benefit in Meningitis

Patients with severe bacterial meningitis were not helped by induced hypothermia in a randomized trial and may actually have been harmed, researchers said.

by John Gever John Gever,Deputy Managing Editor, MedPage Today
October 08, 2013

Action Points

Note that this randomized trial of hypothermia for ICU patients with bacterial meningitis was stopped early with evidence of higher mortality in the hypothermia group.

Be aware that, due to the early stop of the study, robust subgroup analyses were not possible; there may be some patients who would benefit from hypothermia.

Patients with severe bacterial meningitis were not helped by induced hypothermia in a randomized trial and may actually have been harmed, researchers said.

Three months after treatment, 86% of those assigned to hypothermia therapy had unfavorable outcomes -- defined as death or Glasgow Outcome Scale scores of 4 or less -- compared with 74% of patients receiving standard care (RR 2.17, 95% CI 0.78-6.01, P=0.13), according to Bruno Mourvillier, MD, of the Groupe Hospitalier Bichat-Claude Bernard in Paris, and colleagues.

Among the 49 patients in the hypothermia group, 25 died, versus 15 of 49 in the usual-care group (crude RR 1.90, 95% CI 1.29-2.81), the researchers reported online in the Journal of the American Medical Association and at the European Society of Intensive Care Medicine's annual meeting.

After adjusting for age and Glasgow score and the presence of septic shock at randomization, however, the risk of death remained higher in the hypothermia group but was no longer statistically significant (HR 1.76, 95% CI 0.89-3.45, P=0.10).

The trial's data safety and monitoring board stopped the trial early -- the investigators had planned to enroll a total of 318 patients -- when the excess mortality with hypothermia was seen in the first 98 participants.

"Careful evaluation of safety issues in future trials on hypothermia are needed and may have important implications in patients presenting with septic shock or stroke," Mourvillier and colleagues wrote in their JAMA report.

Death rates and poor long-term outcomes with bacterial meningitis are always high, the researchers noted. Past studies have put mortality at about 15%-20%.

Hypothermia has gained attention as a potential approach to reducing that figure mostly on the basis of animal studies, Mourvillier and colleagues indicated. Clear benefits in surrogate outcomes such as intracranial pressure, apoptosis, markers of brain injury, and cytokine cascade initiation were seen in those studies.

In addition, hypothermia has shown clinical benefit in some other conditions that share features with bacterial meningitis, such as cerebral hypoxemia secondary to cardiac arrest. Case reports of successful meningitis treatment with hypothermia have further fueled interest, Mourvillier and colleagues wrote.

Their trial was conducted at 49 centers in France from February 2009 to November 2011. The intervention consisted of cold saline infusions to reduce core body temperatures to 32-34° C for 48 hours, followed by passive warming.

In other respects, patients assigned to the therapy were treated the same as the control group, in which treatment followed published guidelines: appropriate antibiotic therapy and maintenance of arterial pressure and blood CO2, electrolytes, and glucose at recommended levels.

The study's primary outcome measure was Glasgow score at 3 months. Prior to adjustment for baseline parameters, the results were as follows:

Age and the presence of septic shock at randomization were both significantly associated with mortality. Each 10-year increment in age increased the 3-month risk of death by 25% (HR 1.25, 95% CI 1.01-1.55); septic shock more than doubled the mortality risk (HR 2.54, 95% CI 1.31-4.94).

The pattern of outcomes was not markedly different in the 75 patients with pneumococcal meningitis versus those with other etiologies, the researchers found.

Mourvillier and colleagues had no firm explanation for the apparent excess deaths with hypothermia. The treatment did not seem to affect serum electrolytes much differently from usual care, although median sodium concentrations were higher in the intervention group early in the study. Nevertheless, the researchers considered it unlikely that the saline infusions used to induce hypothermia were themselves toxic.

Because the study was halted well before the planned enrollment of 318 patients, it had "low statistical power, precluding robust subgroup analysis and assertion of a smaller harm effect of hypothermia," the researchers wrote. They also noted that hospital personnel were not blinded to treatment assignments.

One other limitation to the study was "heterogeneity of timeline from disease onset to treatment," which could have biased the results.

The study was funded by the French Ministry of Health, IST Cardiology, and Covidien.

Study authors declared they had no relevant financial interests.

Reviewed by F. Perry Wilson, MD, MSCE Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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